SUMMARY Influenza virus infection is one of the most common acute respiratory diseases and remains one of the largest disease burdens on humans, with severe primary viral pneumonia often resulting in death. The pathogenicity of influenza includes a host response that can include a severe systemic inflammatory reaction (cytokine storm) and ensuing vascular leak. Vascular leak is a fundamental element in the pathogenesis of circulatory shock and multiple organ failure, which can lead to death in influenza patients.The laboratories of Dr.DeanLi,co-founderandformerChiefScientificOfficerofNavigen,andDr.ShannonOdelberg,alongwith Navigen, have demonstrated that vascular leak associated with inflammation is mediated by activation of the smallGTPase,ARF6,acommonnodalpointinthesignalingpathwaysofseveralinflammatorycytokinesand growthfactors.Navigen?sobjectiveistoreducemorbidityandmortalityassociatedwithinfluenzainfectionsby modifying this host response. Specifically, we propose to evaluate the efficacy of our small-molecule ARF6 inhibitors with the hypothesis that inhibition of ARF6 will reduce vascular leak elicited by the infection while havingnoadverseeffectonimmunity-basedclearanceofthevirus.